tbuckley/cabot-search huggingface dataset:
PATH-32. CONCORDANCE FOR CDKN2A/B LOSS AND TERT MUTATION IN WHO 2021 CLASSIFICATION GRADE 3 MENINGIOMAS: A RETROSPECTIVE STUDY
Authors: Carlen Yuen, Peter Pan, Damian Teasley, Michael Miller, Yu Sun, Peter Canoll, Adela Joanta-Gomez, Alicia Bargo, Fabio Iwamoto
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The new WHO 2021 classification included CDKN2A/B loss and TERT mutation as new criteria for Grade 3 meningiomas, but excluded H3K27me3 loss. Malignant behavior may be influenced by DNA methyltransferases (DNMT3A). SUFU mutations may carry a predisposition for multiple meningiomas. METHODS In this retrospective study, 228 patients with Grade 2, Grade 3 or recurrent Grade 1 meningiomas with resections from 1990 to July 2021 at Columbia University Medical Center were assessed for recurrence, histologic features, and molecular alterations. RESULTS Of 228 patients with meningiomas, 9 were recurrent Grade 1, 9 were Grade 1 transformed to Grade 2, 109 were non-recurrent Grade 2, 77 were recurrent Grade 2, 13 were transformed Grade 2 to Grade 3, and 5 were non-recurrent Grade 3 and 6 were recurrent Grade 3. Median follow-up was 42.0 months. Of the recurrent/transformed tumors, 89 were radiation-resistant. Average mitotic counts for non-recurrent Grade 2 vs. recurrent/transformed Grade 2 and non-recurrent Grade 3 vs. recurrent Grade 3 meningiomas were 4 vs. 5, 24 vs. 27 mitoses/10HPF, respectively. Of 36 meningiomas evaluated with NGS, the most common alterations was NF2 (20/36). CDKN2A/B was lost in 5 meningiomas, three with Grade 2 that transformed to Grade 3 and two with recurrent disease. TERT was mutant in 3/36, 2 of which were Grade 2 that transformed to Grade 3 meningiomas. H3K27M me3 was tested by IHC in 4 patients, 3 with retained staining, all of whom did not recur and 1 with loss of staining in a Grade 1 transformed to Grade 2. DNMT3A was found in 2 tumors, both radiation-induced. SUFU occurred in 3/16, one of each grade, all solitary. CONCLUSION In our limited cohort, we observed concordance with the new WHO 2021 criteria for Grade 3 meningiomas
EPCO-41. DNA METHYLATION PROFILING OF MENINGIOMAS FROM 17 PATIENTS, A CASE SERIES
Authors: Erica Shen, Nathan Leclair, Kristi Herlth, Melissa Soucy, Nick Renzette, Xinming Zhuo, Kevin Kelly, Gregory Omerza, Leo Wolansky, Kevin Becker, Lei Li, Qian Wu, Ketan Bulsara
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Meningiomas are the most common intracranial tumors. According to the World Health Organization’s (WHO) classification guidelines, they can be classified into 15 subtypes with three grades of malignancy based on histology alone. In recent years, analysis of tumor methylomes that reflects both cell-origin methylation signatures and somatically acquired DNA methylation changes has been utilized to better classify meningiomas with great success. Method: In our case series, we report DNA methylation profiling on meningiomas from 17 patients. Formalin fixed paraffin embedded (FFPE) meningioma tumor samples were processed, loaded onto the Infinium Methylation EPIC array, and scanned using the Illumina IScan system. Raw IDAT files were then processed through the v12b6 version of the CNS tumor classifier developed by the Molecular Neuropathology group at the University of Heidelberg. Classifier output consisted of assigned methylation classifications along with confidence scores, with scores ≥0.84 classified as “high confidence.” Result: Among our meningioma samples from 17 patients (18 samples total), 14 samples are classified as “benign,” one sample is classified as “intermediate,” and the remaining three samples from two patients are classified as “malignant.” In addition to tumor methylation profiling, we also present information that includes patient demographics, clinical presentations, tumor characteristics (size, location), surgical approaches, and mutational analysis. Genomic analysis has revealed variants in NF2, SLX4, ARID1A, KDM4C, ERCC2, EP300, ERBB2, KMT2D, LRP1B, FANCE, CRKL, and SPEN in multiple patients. The three meningioma samples from the two patients that are classified as “malignant” all have a high MIB1 indexes consistent with WHO Grade II meningiomas. Both patients had tumor recurrence reflecting the aggressiveness of the tumor in their disease course. CONCLUSION In accordance with prior reports, our case series provides support that tumor DNA methylation profiling can provide useful classification information and can be correlated to both tumor pathology and patient clinical presentation.
STEM-10. TEMPORAL MULTI-MODAL SINGLE-CELL ANALYSES REVEAL DYNAMIC INTERACTIONS BETWEEN GLIOBLASTOMA AND CAR-T CELLS AND IMMUNOLOGIC MODULATORS OF CANCER STEM CELL STATE
Authors: Daniel Zhang, Xin Wang, Yusha Sun, Donald O'Rourke, Guo-Li Ming, Hongjun Song
Journal: Neuro-Oncology (2022)

Abstract CAR-T cell therapy is a promising new immunotherapy for a number of difficult-to-treat cancers, however, it has yet to yield broad success in glioblastoma (GBM). In particular, tumor heterogeneity presents a major therapeutic challenge, and a detailed understanding of the complex interplay between different neoplastic, non-neoplastic, and CAR-T cells is critical for developing better treatments. Using a patient-derived GBM organoid model of CAR-T cell therapy, we performed single-cell multi-omics to examine the longitudinal dynamics of the adaptive tumor response, changes in cell states, and evolution of cell-to-cell interaction networks. We find that all tumor cell types - neoplastic and non-neoplastic - respond to CAR-T cell activity, and they generate to an initially anti-tumor, but subsequently pro-tumor and immune-inhibitory microenvironment, which is accompanied by eventual CAR-T cell dysfunction and exhaustion. Unexpectedly, CAR-T cell activity also leads to attenuation of glioma stem-like states in both antigen-positive and antigen-negative neoplastic cells and reduces their proliferation via diffusible factors, of which IFNɣ is required but not sufficient. These findings are supported by analyses in patient samples from CAR-T cell therapy clinical trials, and they are consistent across both de novo and recurrent tumors with different somatic mutational landscapes. Our study unravels how the complex heterogeneity of GBM interacts with CAR-T cell therapy, and we identify previously unappreciated possibilities to affect antigen-negative neoplastic cells in ways that may be further augmented for enhanced therapeutic efficacy.
QOL-23. TOWARDS PATIENT-REPORTED OUTCOME ASSESSMENT IN THE MOLECULAR TUMOR BOARD – CANCER PATIENTS UNDER TARGETED THERAPY: APP-BASED ASSESSMENT OF PATIENT-REPORTED OUTCOMES (TRACE)
Authors: Mirjam Renovanz, Paula Bombach, Lucia Grosse, Johannes Rieger, Marco Skardelly, David Rieger, Hanni Hille, Sebastian Volkmer, Lorenz Dörner, Sylvia Kurz, Melina Hippler, Frank Paulsen, Öznur Öner, Kristina Ruhm, Janina Beha, Holly Sundberg-Malek, Yvonne Möller, Marcos Tatagiba, Markus Wallwiener, Nils Eckert, Pascal Escher, Nico Pfeiffer, Andrea Forschner, Armin Bauer, Daniel Zips, Michael Bitzer, Nisar Malek, Cihan Gani, Ghazaleh Tabatabai
Journal: Neuro-Oncology (2022)

Abstract Comprehensive genomic profiling and biomarker-based therapeutic strategies are currently used in clinical trials and in innovative health care systems including the center for personalized medicine network. Systematic assessments of patient-reported outcomes are warranted to gain insight into the perspective of patients and their relatives during biomarker-based therapies. In the present study, we focused on health-related quality of life (HRQoL), psychosocial situation, and physical symptoms in patients treated at the Center for Personalized Medicine Tübingen. First, we retrospectively evaluated symptom burden of n=265 (neuro-)oncological patients in the Molecular Tumor Board (MTB). Sixty percent of patients reported at least 1 neurological symptom, and psychosocial burden/unmet needs were high (overall 156/265; 59%, patients with malignant tumors n=86/106; 81%, Fisher’s exact, p &amp;lt; 0.0001). We therefore developed an app by 14 expert rounds and pretesting including validated assessments of HRoL, symptom und psychological burden and tested it in a pilot study. We conducted a structured interview with users 3 months afterwards to assess the app’s usability and feasibility. The interview was transcribed and analyzed according to a qualitative content analysis. So far, a total of 10 patients and caregivers have been enrolled in this pilot study. They reported that (i) the app is compatible with their daily routine (median 9.3, range 0-10), that (ii) they are more aware of their health status, which was rated as positive, and that (iii) completing app-based questionnaires was easier compared to paper questionnaires. Two patients reported technical problems, which were resolved timely. The pilot study proved feasibility and acceptance of the app. The app might optimize symptom burden assessment, adapted to the patients’ profiles. The next step is to prospectively compare HRQoL before and after start of targeted therapy in a multicenter study.
INNV-21. FEASIBILITY OF A VIRTUAL REALITY (VR) INTERVENTION TARGETING DISTRESS AND ANXIETY IN PRIMARY BRAIN TUMOR (PBT) PATIENTS AT THE TIME OF NEUROIMAGING: INTERIM ANALYSIS OF A PHASE 2 CLINICAL TRIAL
Authors: Amanda King, Kayla Roche, Heather Leeper, Elizabeth Vera, Tito Mendoza, Kelly Mentges, Alvina Acquaye, Kendra Adegbesan, Lisa Boris, Eric Burton, Claudia Chambers, Anna Choi, Alexa Christ, Karen Evans, Ewa Grajkowska, Jason Levine, Matthew Lindsley, Nicole Lollo, Edina Komlodi-Pasztor, Hope Miller, Marissa Panzer, Marta Penas-Prado, Valentina Pillai, Lily Polskin, Jennifer Reyes, James Rogers, Solmaz Sahebjam, Dilorom (Delia) Sass, Dorela Shuboni-Mulligan, Macy Stockdill, Brett Theeler, Kathleen Wall, Alex Wollet, Jing Wu, Mark Gilbert, Terri Armstrong
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND PBT patients experience high levels of distress and anxiety symptoms at the time of neuroimaging, yet few non-pharmacological interventions are available. This phase 2 clinical trial interim analysis explored feasibility of a VR relaxation intervention for a PBT population. METHODS PBT patients seen at NIH were recruited to participate in this single arm trial conducted via telehealth. English-speaking, adult patients with upcoming neuroimaging who can self-report symptoms and have reported distress on previous MD Anderson Symptom Inventory-Brain Tumor assessments were eligible. Exclusion criteria include recent surgery or seizures, anxiety disorders, nausea, or visual deficits. The primary intervention consisted of a brief VR session done within 2 weeks prior to neuroimaging with patient-reported outcomes (PROs) collected before and immediately post-intervention, as well as 1 week and 4 weeks later, with self-directed VR use over 1 month. A qualitative phone interview was also completed to assess patient satisfaction. RESULTS Fifty-five patients were screened and approached with 40 (73%) responding to initial reach-out and 20 ultimately enrolling (9 declines, 11 screen fails). Decline reasons included: no distress/anxiety (30%), treatment-related toxicities (11%), and unknown (59%). Seven (64%) failed screening due to exclusionary anxiety disorders (36% GAD, 18% PTSD, 9% claustrophobia). Of those enrolled, 65% were ≤ 50 years, 50% were male, 90% were White/non-Hispanic, 85% had good KPS ( &amp;gt; 80), 65% had high-grade tumors, and most were on active treatment. All enrolled patients completed the VR intervention and participation period, PROs questionnaires, weekly check-ins, and qualitative interview. Most patients (90%) reported frequent VR use with 7 mild adverse effects reported (headache, dizziness, nausea, neck pain). CONCLUSION These findings suggest that this intervention is feasible for this population with high enrollment and study completion, though incidence of anxiety disorders was higher than anticipated and a comprehensive evaluation of this cohort is planned.
CNSC-31. CRISPR FUNCTIONAL SCREEN IDENTIFIES A NOVEL LONG NONCODING RNA MODULATING GLIOBLASTOMA INVASION
Authors: Kathleen Tsung, Jane Han, Kristie Liu, Eddie Loh, Frank Attenello
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Glioblastoma(GBM) invasion studies traditionally target coding genes. Long noncoding RNAs (lncRNAs), are transcripts without coding potential, with limited data regarding function. We leveraged CRISPR-interference, repressing lncRNA transcription via Cas9-KRAB, to evaluate invasive function of GBM-associated lncRNAs in a CRISPRi functional screen. METHODS 2,307 candidate lncRNAs were assembled from GBM differential gene expression. Guide RNAs targeting candidates were lentivirally incorporated into GBM screening populations. Screen populations were evaluated via Matrigel invasion, comparing sgRNA populations before/after a 24-hour invasion period. ASO treatment evaluated pharmacologic targeting of candidate lncRNAs. Top screening candidates were evaluated in a patient derived glioma stem cell (GSC) line, USC02, as well as U87 and U251 commercial lines. Differential gene expression was assessed in multiple cell lines following lncRNA knockdown via RNA-seq followed by GSEA and pathway analysis was evaluated to assess downstream mechanistic candidates affected by lncRNA KD. RESULTS Forty-eight lncRNAs were significantly associated with GBM invasion, with lncRNA repression associated with decreased invasion of 31-85%(p&amp;lt; 0.01). Individual validation of a candidate lncRNA KD, LH02236, confirmed 85% decrease in tumor cell invasion versus control. Evaluation of gene expression across normal cortex and tumor samples from GSEA/TCGA datasets revealed LH02236 is significantly more expressed in GBM versus low grade glioma, and in low grade glioma versus normal cortex. Expression of LH02236 was significantly associated with patient survival (p&amp;lt; 0.0001). Gene expression analysis of LH02236 knockdown revealed Sox10 to be highly correlated with lncRNA expression across multiple cell lines. CONCLUSION Large scale CRISPRi screening identified LH02236, a previously unannotated lncRNA, as essential to invasion in patient lines. Gene expression is significantly associated with tumor grade and patient survival. Analysis of knockdown across multiple cell lines suggests Sox 10, commonly associated with GSC function, is modulated by this novel lncRNA.
BIOM-01. GENOMIC ALTERATIONS IN ALK FUSION-POSITIVE NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS WITH BRAIN METASTASES
Authors: Jordan Eichholz, Emily Miao, Emily Lebow, Henry Walch, Jessica Flynn, Zhigang Zhang, Harper Hubbeling, Kathryn Beal, Nelson Moss, Kenny Yu, Jonathan Yang, Alicia Meng, Daniel Kelly, Thomas Boerner, Daniel Gomez, Andreas Rimner, Nikolaus Schultz, Alexander Drilon, Brandon Imber, Luke Pike
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Brain metastases (BM) are common in patients with anaplastic lymphoma kinase fusion-positive NSCLC (ALK+ NSCLC). We characterized the genomics of patients with ALK+ NSCLC BM treated with alectinib with or without local therapy to identify correlations of co-mutations with CNS-specific outcomes. METHODS We retrospectively reviewed ALK+ NSCLC patients with BMs who received alectinib for the definitive treatment of BM from 1/2012 and 5/2021. Genomic characteristics of 27 specimens from 27 patients were assessed with MSK-IMPACT, a 505-gene next-generation sequencing (NGS)-based tumor sequencing assay with &amp;gt;700x coverage. Intracranial progression-free survival (iPFS) and overall survival (OS) from BM diagnosis were analyzed using standard statistical methods. RESULTS The median age at BM diagnosis was 57 years (range 25-83). Median iPFS was 1.94 years (95%CI: 1.58- not reached) and median OS was 6.08 years (95%CI: 1.7– not reached). All patients received alectinib for the treatment of brain metastases (78% as 1st-line TKI) and 22% received local therapy. The most frequently altered co- alterations were CDKN2A (48%), TP53 (22%), MAP2K4 (15%), SMARCA4 (11%), CREBBP (11%), and ATM (7%). CDKN2A alterations were more common in patients with intracranial progression (64% vs 31%). MAP2K4 alterations were enriched in metastatic samples (p = 0.028, q = 0.113). SMARCA4 co- alterations were associated with inferior OS (HR: 8.76, 95%CI = 1.74-44.2, p= 0.009) and trended toward association with iPFS but was insignificant (HR: 3.25, 95%CI = 0.83-12.4, p=0.089). We identified missense ALK alterations in CSF from a patient who acquired resistance to alectinib and had leptomeningeal progression (G1269A, I1171T, L1108P). CONCLUSION This study is the first analysis of CNS specific outcomes with detailed genomic annotation for ALK+ NSCLC patients who received definitive alectinib for BM. Further investigation into the role of CNS-penetrant TKIs and the genomic alterations predictive of CNS failure are needed.
NCOG-44. FAMILY CAREGIVER CONSTRUCTS AND OUTCOMES IN NEURO-ONCOLOGY: A SYSTEMATIC REVIEW
Authors: Florien Boele, Caroline Hertler, Linda Dirven, Karin Piil, Paula Sherwood
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND As a first step to reach consensus on the key constructs and outcomes in neuro-oncology caregiver research, we performed a systematic review to evaluate the constructs that are being evaluated in research studies and how these have been assessed. METHODS All peer-reviewed publications with primary data reporting on outcomes of family caregivers of adult primary brain tumour patients were eligible. Electronic databases PubMed/ Medline, Embase, Web of Science, Emcare, Cochrane Library, and PsycINFO were searched up to September 2021. Using Covidence, title and abstract screening, full text review, and data extraction were done by two researchers independently, with a third guiding consensus. Constructs as reported in each study, and how these were assessed were the primary result. RESULTS Searches yielded 1090 unique records, with 213 remaining after title/abstract screening. Of these, 157 publications met inclusion criteria, comprising 120 unique studies. These originated from 18 countries and were published between 1996-2022. Most were observational (75%) cross-sectional (61%) studies, reporting on quantitative methods (62%). Twenty-seven different constructs were assessed and mapped along the Caregiver Health Model categories: caregiver health, needs, tasks, beliefs and attitudes, and environment. Seventeen questionnaires were used &amp;gt; 2 times to measure the same construct, with the vast majority of questionnaires only used across one or two studies. DISCUSSION Neuro-oncology caregiving research is a field gaining traction, but lags behind in clear definition of key constructs, and consistency in assessment of these constructs. Developing consensus or guidance will improve comparability of studies, meta-analyses, and advance the science more quickly.
TMET-21. ENHANCING THE METABOLIC FITNESS OF T CELLS TO TREAT BRAIN TUMORS
Authors: Tanya Ghosh, Linchun Jin, Diana Feier, Aryeh Silver, Guimei Tian, Mariana Dajac, Maryam Rahman, Catherine Flores, Matthew Sarkisian, Jianping Huang, Duane Mitchell, Loic Deleyrolle
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Glioblastoma is a challenge for neuro-oncologists and current therapies are minimally effective. Standard-of- care treatment is almost inevitably followed by disease recurrence. Adoptive T cell transfer has emerged as a viable therapeutic for brain malignancies. While promising, the efficacy of this approach is often limited by a complex immunosuppressive tumor microenvironment. These complexities mean that more sophisticated T cell products are required. Objectives: The brain tumor microenvironment provides local restraints via metabolic competition suppressing antitumor immunity, specifically inhibiting infiltration and tumoricidal functions of host and adoptively transferred tumor-reactive T cells. The overall goal of this project is to test new treatments to reverse immune dysfunction in cancer through the regulation of T cell metabolic signaling. We propose that modulating the glucose pathway in T cells can potentiate their anti-tumor activity once adoptively transferred. METHODS The glucose metabolic pathway of T cells was modulated via overexpression of glucose transporters. The functionality of metabolically modified T cells was investigated in murine and human models. RESULTS We demonstrated the existence of a competition for glucose between T cells and tumor cells, with tumor cells imposing glucose restriction mediating T cell hyporesponsiveness. Overexpression of glucose transporters such as Glut1 and Glut3 increased T cell glucose utilization and provided a survival/growth advantage and enhanced T cell activation in glucose-restricted conditions. We also established that glucose transporter overexpression improves intratumoral infiltration and expansion of adoptively transferred T cells, resulting in improved survival. CONCLUSION This project integrates fundamental concepts of tumor and immune metabolism in the design of immunotherapy and confirms that immunometabolism represents a viable target for new cancer therapy to treat brain tumors.
EXTH-100. EVALUATION OF PANOBINOSTAT PLASMA AND CEREBROSPINAL FLUID (CSF) PHARMACOKINETIC PROFILE FOLLOWING ADMINISTRATION OF THE CAPSULE FORMULATION FARYDAK® IN A NON-HUMAN (NHP) PRIMATE PRECLINICAL MODEL
Authors: Cynthia Lester McCully, Katherine Warren, Sara Zimmerman, Cody Peer, Kristin Killoran, Rafael Cruz Garcia, William Figg, Brigitte Widemann
Journal: Neuro-Oncology (2022)

Abstract Panobinostat is an HDAC inhibitor with dose-dependent pre-clinical activity against pediatric glioma. Reported pharmacokinetic (PK) profiles of panobinostat, including CSF penetration, have varied. We hypothesized that this variability resulted from the utilization of differing panobinostat formulations. For comparison to the USP grade powdered formulation PK profile formerly reported (Rodgers, et al., Cancer Chemother Pharmacol. 2020 Apr;85(4):827-830) a plasma and CSF PK study was conducted with panobinostat administered as the capsule formulation, Farydak®, utilizing the same non-human primate (NHP) model, study design, analytical methods, and analysis. METHODS Three NHP previously developed for serial CSF access via a lateral ventricular CSF reservoir (n=2), or lumbar CSF port (n=1) received panobinostat orally (1.6 mg/kg, Human Dose Equivalent: 32 mg/m2) followed by serial paired plasma and CSF sample collections from 0-72 hours. Samples were quantified by LC-MS/MS. PK parameters were determined via noncompartmental analysis. RESULTS Mean plasma and CSF PK parameters Tmax (h), Cmax (nM), and AUCinf (h*nM/mg) are reported and compared to the corresponding PK parameters from the USP grade powdered formulation study formerly reported. Capsule Formulation: Plasma - Tmax: 5.3 □ 1.2, Cmax: 20 □ 1.9, AUClast: 14.5 □ 11.1, AUCinf: 15.2 □ 11.4 CSF - Tmax: 5.0 □ 3.6, Cmax: 1.7 □ 0.3, AUClast: 0.54 □ 0.47, AUCinf: unable to calculate Powdered Formulation – Mean PK of all dose levels formerly reported: Plasma -Tmax: 1.06 □ 0.13, Cmax: 1.27 □ 0.6, AUCinf: 7.7 □ 2.7 CSF - Cmax and Tmax: Unable to determine. Single quantifiable sample across all studies. AUCinf: unable to calculate. CONCLUSION The plasma and CSF Tmax, Cmax, the plasma AUCinf, and the CSF AUClast for panobinostat were increased following oral administration of the capsule formulation of panobinostat, Farydak®, compared to USP grade powder formulation of the drug.